The Microenvironment as a Target for Therapy in Chronic Lymphocytic Leukemia

Review Article

Austin J Cancer Clin Res 2014;1(3): 1014.

The Microenvironment as a Target for Therapy in Chronic Lymphocytic Leukemia

Herishanu Yair1,2,3*#, Perry Chava1,3# and Katz Ben-Zion1,2

11Department of Hematology, Tel Aviv Sourasky Medical Center, Israel

22Sackler Faculty of Medicine, Tel-Aviv University, Israel

3Both authors contributed equally

*Corresponding author: Yair Herishanu, Department of Hematology, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel-Aviv, Israel.

Received: May 26, 2014; Accepted: June 14, 2014; Published: June 17, 2014


One of the hallmarks of malignant cells is the deregulation of their growth, survival and differentiation. In the case of Chronic Lymphocytic Leukemia (CLL), cellular physiology is regulated, to a large extent, by micro environmental elements that operate within the bone marrow and secondary lymphoid tissues. Extracellular cues that are vital for CLL cells survival and proliferation are exerted by interactions of CLL cells with accessory cells such as T-cells, mesenchymal stromal cells, endothelial cells, follicular dendritic cells and macrophages. CLL cells interact directly with effect or cells via a variety of adhesion molecules, while cytokines, chemokines, enzymes and growth factors provide a complex soluble regulatory network. The B-cell receptor (BCR) is the central source of signals that regulate CLL cells physiological responses. These signals can be triggered by the engagement of the receptor by extracellular antigens of either of microbial origin or auto antigens. Alternatively, as has been revealed in the recent years, the BCR can be activated by ligand-independent cell-autonomous signaling mechanisms. Due to its prime importance in CLL physiology, the biochemical array that mediates micro environmental-derived signaling responses in CLL cells became a useful target for the development of novel effective therapeutics. For example, small molecule inhibitors of SYK, BTK, or PI3K6, all participate in BCR signaling responses, have shown remarkable Clinical effects. Also, BCL-2 inhibitors and immune modulatory drugs are being tested in clinical trials in CLL, with encouraging results. Hence, better understanding of CLL cells’ interaction with the microenvironment can continuously provide clinicians with novel effective therapeutics to control CLL.


Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in the Western world. It is an indolent lymphoproliferative disorder characterized by the progressive accumulation of monoclonal, small, mature-appearing CD5+ B-cells in the peripheral blood, bone marrow and secondary lymphoid tissues [1]. CLL is currently an incurable disease, with the possible exception of patients undergoing allogeneic stem cell transplantation [2]. The present standard chemotherapy and/or immunotherapy eradicate CLL cells from the peripheral blood more efficiently than from the lymphoid tissues and bone marrow, the latter two sites are assumed to harbor the cells from which future recurrences will originate from.

Recent work has shown that CLL cells are tightly supported by their tissue microenvironment. This is based on two fundamental observations: First, ex-vivo cultured CLL cells rapidly undergo apoptosis but can be rescued by contact with stromal cells [3,4]. Second, CLL cells in the peripheral blood are arrested in G0/G1 phase of the cell cycle [5], while they proliferate in the bone marrow and secondary lymphoid tissues, in areas termed ‘pseudo follicles’ or ‘proliferation centers’ [6,7]. Such compartmental differences are explained by antigenic engagement and interactions with a variety of accessory cells and exposure to different chemokines, cytokines and extracellular matrix components in tissue compartments (Figure1).

Major progress has been made in our understanding of the cross-talk between CLL cells and the surrounding microenvironment. In this review, we will summarize these interactions in the context of novel drugs that target CLL pathophysiology.

The Microenvironment

B-cell receptor (BCR) signaling

BCR signaling is a crucial component in normal B-cells development as well as in the pathogenesis of CLL [8], where it seems to play a pivotal role in protecting CLL cells from apoptosis [8,9], and promoting their entry into cell cycle [10,11].

Patients with CLL can be divided into two main subgroups based on the presence or absence of somatic mutations in the variable region of the immunoglobulin heavy chain gene (IGHV) expressed by the malignant cells [12,13]. Patients with the mutated IGHV CLL subtype follow an indolent clinical course, whereas the subgroup of un mutated IGHV tend to have a more aggressive disease [12,13]. CLL cells use a restricted repertoire of IGHV genes, indicating a role for antigen selection in the evolution of this disease [14,15]. Some patients express almost identical BCRs, known as “stereotyped BCRs”, that recognize common antigens [16-18]. These antigens are still incompletely known but are assumed to include microbial antigens and auto antigens derived from dying cells [19-21]. Recently, Duhren-von Minden and colleagues suggested that epitopes in the framework region of surface immunoglobulin’s expressed on CLL cells act as auto antigens and auto-stimulate the malignant cells [22]. Thus, in addition to antigen-mediated stimulation, the BCR may also be activated by ligand-independent cell-autonomous signaling in CLL cells.

Citation: Yair H, Chava P and Ben-Zion K. The Microenvironment as a Target for Therapy in Chronic Lymphocytic Leukemia. Austin J Cancer Clin Res 2014;1(3): 1014. ISSN 2381-909X